tbuckley/cabot-search huggingface dataset:
Aptamer Proteomics for Biomarker Discovery in Heart Failure With Reduced Ejection Fraction
Authors: Luqing Zhang, Jonathan W. Cunningham, Brian L. Claggett, Jaison Jacob, Michael M. Mendelson, Pablo Serrano-Fernandez, Sergio Kaiser, Denise P. Yates, Margaret Healey, Chien-Wei Chen, Gordon M. Turner, Natasha L. Patel-Murray, Faye Zhao, Michael T. Beste, Jason M. Laramie, William T. Abraham, Pardeep S. Jhund, Lars Kober, Milton Packer, Jean Rouleau, Michael R. Zile, Margaret F. Prescott, Martin Lefkowitz, John J.V. McMurray, Scott D. Solomon, William Chutkow
Journal: Circulation (2022)
Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER
Authors: Pardeep S. Jhund, Toru Kondo, Jawad H. Butt, Kieran F. Docherty, Brian L. Claggett, Akshay S. Desai, Muthiah Vaduganathan, Samvel B. Gasparyan, Olof Bengtsson, Daniel Lindholm, Magnus Petersson, Anna Maria Langkilde, Rudolf A. de Boer, David DeMets, Adrian F. Hernandez, Silvio E. Inzucchi, Mikhail N. Kosiborod, Lars Køber, Carolyn S. P. Lam, Felipe A. Martinez, Marc S. Sabatine, Sanjiv J. Shah, Scott D. Solomon, John J. V. McMurray
Journal: Nature Medicine (2022)

Abstract Whether the sodium–glucose cotransporter 2 inhibitor dapagliflozin reduces the risk of a range of morbidity and mortality outcomes in patients with heart failure regardless of ejection fraction is unknown. A patient-level pooled meta-analysis of two trials testing dapagliflozin in participants with heart failure and different ranges of left ventricular ejection fraction (≤40% and &gt;40%) was pre-specified to examine the effect of treatment on endpoints that neither trial, individually, was powered for and to test the consistency of the effect of dapagliflozin across the range of ejection fractions. The pre-specified endpoints were: death from cardiovascular causes; death from any cause; total hospital admissions for heart failure; and the composite of death from cardiovascular causes, myocardial infarction or stroke (major adverse cardiovascular events (MACEs)). A total of 11,007 participants with a mean ejection fraction of 44% (s.d. 14%) were included. Dapagliflozin reduced the risk of death from cardiovascular causes (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76–0.97; P = 0.01), death from any cause (HR 0.90, 95% CI 0.82–0.99; P = 0.03), total hospital admissions for heart failure (rate ratio 0.71, 95% CI 0.65–0.78; P &lt; 0.001) and MACEs (HR 0.90, 95% CI 0.81–1.00; P = 0.045). There was no evidence that the effect of dapagliflozin differed by ejection fraction. In a patient-level pooled meta-analysis covering the full range of ejection fractions in patients with heart failure, dapagliflozin reduced the risk of death from cardiovascular causes and hospital admissions for heart failure (PROSPERO: CRD42022346524).
Efficacy and Safety of Dapagliflozin According to Frailty in Patients With Heart Failure: A Prespecified Analysis of the DELIVER Trial
Authors: Jawad H. Butt, Pardeep S. Jhund, Jan Belohlávek, Rudolf A. de Boer, Chern-En Chiang, Akshai S. Desai, Jarosław Drożdż, Adrian F. Hernandez, Silvio E. Inzucchi, Tzvetana Katova, Masafumi Kitakaze, Mikhail N. Kosiborod, Carolyn S.P. Lam, Anna Maria Langkilde, Daniel Lindholm, Erasmus Bachus, Felipe Martinez, Béla Merkely, Magnus Petersson, Jose F. Kerr Saraiva, Sanjiv J. Shah, Muthiah Vaduganathan, Orly Vardeny, Ulrica Wilderäng, Brian L. Claggett, Scott D. Solomon, John J.V. McMurray
Journal: Circulation (2022)

Frailty is increasing in prevalence. Because patients with frailty are often perceived to have a less favorable risk/benefit profile, they may be less likely to receive new pharmacologic treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure with mildly reduced or preserved ejection fraction randomized in DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure).
LNP-mediated delivery of CRISPR RNP for wide-spread in vivo genome editing in mouse cornea
Authors: Seyedeh Zeinab Mirjalili Mohanna, Diana Djaksigulova, Austin M. Hill, Pamela K. Wagner, Elizabeth M. Simpson, Blair R. Leavitt
Journal: Journal of Controlled Release (2022)

CRISPR/Cas9-based genome-editing therapies are poised to change the clinical outcome for many diseases with validated therapeutic targets awaiting an appropriate delivery system. Recent advances in lipid nanoparticle (LNP) technology make them an attractive platform for the delivery of various forms of CRISPR/Cas9, including the efficient and transient Cas9/gRNA ribonucleoprotein (RNP) complexes. In this study, we initially tested our novel LNP platform by delivering pre-complexed RNPs and template DNA to cultured mouse cortical neurons, and obtained successful ex vivo genome editing. We then directly injected LNP-packaged RNPs and DNA template into the mouse cornea to evaluate in vivo delivery. For the first time, we demonstrated wide-spread genome editing in the cornea using our LNP-RNPs. The ability of our LNPs to transfect the cornea highlights the potential of our novel delivery platform to be used in CRISPR/Cas9-based genome editing therapies of corneal diseases.
SGLT2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials
Authors: Muthiah Vaduganathan, Kieran F Docherty, Brian L Claggett, Pardeep S Jhund, Rudolf A de Boer, Adrian F Hernandez, Silvio E Inzucchi, Mikhail N Kosiborod, Carolyn S P Lam, Felipe Martinez, Sanjiv J Shah, Akshay S Desai, John J V McMurray, Scott D Solomon
Journal: The Lancet (2022)
Influence of NT-proBNP on Efficacy of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction
Authors: Peder L. Myhre, Muthiah Vaduganathan, Brian L. Claggett, Zi Michael Miao, Pardeep S. Jhund, Rudolf A. de Boer, Adrian F. Hernandez, Silvio E. Inzucchi, Mikhail N. Kosiborod, Carolyn S.P. Lam, Felipe Martinez, Sanjiv J. Shah, Akshay S. Desai, Daniel Lindholm, Magnus Petersson, Anna Maria Langkilde, John J.V. McMurray, Scott D. Solomon
Journal: JACC Heart Failure (2022)
Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction
Authors: Jonathan W. Cunningham, Muthiah Vaduganathan, Brian L. Claggett, Ian J. Kulac, Akshay S. Desai, Pardeep S. Jhund, Rudolf A. de Boer, David DeMets, Adrian F. Hernandez, Silvio E. Inzucchi, Mikhail N. Kosiborod, Carolyn S.P. Lam, Felipe Martinez, Sanjiv J. Shah, Martina M. McGrath, Eileen O’Meara, Ulrica Wilderäng, Daniel Lindholm, Magnus Petersson, Anna Maria Langkilde, John J.V. McMurray, Scott D. Solomon
Journal: Journal of the American College of Cardiology (2022)

Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death.The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization.The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF >40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death.Of 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P < 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients.Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).
Atrial Fibrillation and Dapagliflozin Efficacy in Patients With Preserved or Mildly Reduced Ejection Fraction
Authors: Jawad H. Butt, Toru Kondo, Pardeep S. Jhund, Josep Comin-Colet, Rudolf A. de Boer, Akshai S. Desai, Adrian F. Hernandez, Silvio E. Inzucchi, Stefan P. Janssens, Mikhail N. Kosiborod, Carolyn S.P. Lam, Anna Maria Langkilde, Daniel Lindholm, Felipe Martinez, Magnus Petersson, Sanjiv J. Shah, Jorge Thierer, Muthiah Vaduganathan, Subodh Verma, Ulrica Wilderäng, Brian L. Claggett, Scott D. Solomon, John J.V. McMurray
Journal: Journal of the American College of Cardiology (2022)

Atrial fibrillation (AF) is common in heart failure (HF), is associated with worse outcomes compared with sinus rhythm, and may modify the effects of therapy.This study examined the effects of dapagliflozin according to the presence or not of AF in the DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trial.A total of 6,263 patients with HF with New York Heart Association functional class II-IV, left ventricular ejection fraction >40%, evidence of structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide levels were randomized to dapagliflozin or placebo. Clinical outcomes and the effect of dapagliflozin, according to AF status, were examined. The primary outcome was a composite of cardiovascular death or worsening HF.Of the 6,261 patients with data on baseline AF, 43.3% had no AF, 18.0% had paroxysmal AF, and 38.7% had persistent/permanent AF. The risk of the primary endpoint was higher in patients with AF, especially paroxysmal AF, driven by a higher rate of HF hospitalization: no AF, HF hospitalization rate per 100 person-years (4.5 [95% CI: 4.0-5.1]), paroxysmal AF (7.5 [95% CI: 6.4-8.7]), and persistent/permanent AF (6.4 [95% CI: 5.7-7.1]) (P < 0.001). The benefit of dapagliflozin on the primary outcome was consistent across AF types: no AF, HR: 0.89 (95% CI: 0.74-1.08); paroxysmal AF, HR: 0.75 (95% CI: 0.58-0.97); persistent/permanent AF, HR: 0.79 (95% CI: 0.66-0.95) (Pinteraction = 0.49). Consistent effects were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the KCCQ-TSS.In DELIVER, the beneficial effects of dapagliflozin compared with placebo on clinical events and symptoms were consistent, irrespective of type of AF at baseline. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure. [DELIVER]; NCT03619213).
Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction
Authors: Scott D. Solomon, John J.V. McMurray, Brian Claggett, Rudolf A. de Boer, David DeMets, Adrian F. Hernandez, Silvio E. Inzucchi, Mikhail N. Kosiborod, Carolyn S.P. Lam, Felipe Martinez, Sanjiv J. Shah, Akshay S. Desai, Pardeep S. Jhund, Jan Belohlavek, Chern-En Chiang, C. Jan Willem Borleffs, Josep Comin-Colet, Dan Dobreanu, Jaroslaw Drozdz, James C. Fang, Marco Antonio Alcocer-Gamba, Waleed Al Habeeb, Yaling Han, Jose Walter Cabrera Honorio, Stefan P. Janssens, Tzvetana Katova, Masafumi Kitakaze, Béla Merkely, Eileen O’Meara, Jose Francisco Kerr Saraiva, Sergey N. Tereshchenko, Jorge Thierer, Muthiah Vaduganathan, Orly Vardeny, Subodh Verma, Vinh Nguyen Pham, Ulrica Wilderäng, Natalia Zaozerska, Erasmus Bachus, Daniel Lindholm, Magnus Petersson, Anna Maria Langkilde
Journal: New England Journal of Medicine (2022)

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain.
DELIVERing Progress in Heart Failure with Preserved Ejection Fraction
Authors: Kenneth B. Margulies
Journal: New England Journal of Medicine (2022)

More than 6 million adults in the United States have heart failure, accounting for at least 800,000 hospitalizations annually.1 More than half of these persons have heart failure with a preserved left ventricular ejection fraction.1 As the population ages, the overall prevalence of patients with heart failure and a preserved ejection fraction is increasing.1,2 Heart failure with a preserved ejection fraction is associated with substantial functional and quality-of-life impairments that are at least equivalent to those of patients with heart failure and a reduced ejection fraction.2 One-year mortality among patients with heart failure and a preserved ejection fraction is between . . .
Connecting telomere maintenance and regulation to the developmental origin and differentiation states of neuroblastoma tumor cells
Authors: Eun Young Yu, Nai-Kong V. Cheung, Neal F. Lue
Journal: Journal of Hematology & Oncology (2022)

Abstract A cardinal feature that distinguishes clinically high-risk neuroblastoma from low-risk tumors is telomere maintenance. Specifically, neuroblastoma tumors with either active telomerase or alternative lengthening of telomeres exhibit aggressive growth characteristics that lead to poor outcomes, whereas tumors without telomere maintenance can be managed with observation or minimal treatment. Even though the need for cancer cells to maintain telomere DNA—in order to sustain cell proliferation—is well established, recent studies suggest that the neural crest origin of neuroblastoma may enforce unique relationships between telomeres and tumor malignancy. Specifically in neuroblastoma, telomere structure and telomerase activity are correlated with the adrenergic/mesenchymal differentiation states, and manipulating telomerase activity can trigger tumor cell differentiation. Both findings may reflect features of normal neural crest development. This review summarizes recent advances in the characterization of telomere structure and telomere maintenance mechanisms in neuroblastoma and discusses the findings in the context of relevant literature on telomeres during embryonic and neural development. Understanding the canonical and non-canonical roles of telomere maintenance in neuroblastoma could reveal vulnerabilities for telomere-directed therapies with potential applications to other pediatric malignancies.
A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma
Authors: Anita D'Souza, Nina Shah, Cesar Rodriguez, Peter M. Voorhees, Katja Weisel, Orlando F. Bueno, Rajvineeth K. Pothacamury, Kevin J. Freise, Susan Yue, Jeremy A. Ross, Akshanth R. Polepally, Chetasi Talati, Shane Lee, Ziyi Jin, Ben Buelow, Ravi Vij, Shaji Kumar
Journal: Journal of Clinical Oncology (2022)

ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study.Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion.As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively.ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.
REVIVE-ing a Weak Heart — Details Matter
Authors: Ajay J Kirtane
Journal: New England Journal of Medicine (2022)

Ischemic cardiomyopathy represents the pathophysiological convergence of two growing clinical problems: atherosclerotic coronary artery disease and congestive heart failure. When a patient presents with congestive heart failure, it is incumbent on clinicians to undertake an etiologic workup that includes evaluation for a diagnosis of coronary artery disease1; simply establishing a diagnosis of coronary artery disease has been associated with greater use of guideline-directed medical therapies among patients with congestive heart failure.2 When it is severe, coronary artery disease is often assumed to be the cause of left ventricular dysfunction. Apart from the accuracy of that assumption, a further open question . . .
Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction
Authors: Divaka Perera, Tim Clayton, Peter D. O’Kane, John P. Greenwood, Roshan Weerackody, Matthew Ryan, Holly P. Morgan, Matthew Dodd, Richard Evans, Ruth Canter, Sophie Arnold, Lana J. Dixon, Richard J. Edwards, Kalpa De Silva, James C. Spratt, Dwayne Conway, James Cotton, Margaret McEntegart, Amedeo Chiribiri, Pedro Saramago, Anthony Gershlick, Ajay M. Shah, Andrew L. Clark, Mark C. Petrie
Journal: New England Journal of Medicine (2022)

Whether revascularization by percutaneous coronary intervention (PCI) can improve event-free survival and left ventricular function in patients with severe ischemic left ventricular systolic dysfunction, as compared with optimal medical therapy (i.e., individually adjusted pharmacologic and device therapy for heart failure) alone, is unknown.We randomly assigned patients with a left ventricular ejection fraction of 35% or less, extensive coronary artery disease amenable to PCI, and demonstrable myocardial viability to a strategy of either PCI plus optimal medical therapy (PCI group) or optimal medical therapy alone (optimal-medical-therapy group). The primary composite outcome was death from any cause or hospitalization for heart failure. Major secondary outcomes were left ventricular ejection fraction at 6 and 12 months and quality-of-life scores.A total of 700 patients underwent randomization - 347 were assigned to the PCI group and 353 to the optimal-medical-therapy group. Over a median of 41 months, a primary-outcome event occurred in 129 patients (37.2%) in the PCI group and in 134 patients (38.0%) in the optimal-medical-therapy group (hazard ratio, 0.99; 95% confidence interval [CI], 0.78 to 1.27; P = 0.96). The left ventricular ejection fraction was similar in the two groups at 6 months (mean difference, -1.6 percentage points; 95% CI, -3.7 to 0.5) and at 12 months (mean difference, 0.9 percentage points; 95% CI, -1.7 to 3.4). Quality-of-life scores at 6 and 12 months appeared to favor the PCI group, but the difference had diminished at 24 months.Among patients with severe ischemic left ventricular systolic dysfunction who received optimal medical therapy, revascularization by PCI did not result in a lower incidence of death from any cause or hospitalization for heart failure. (Funded by the National Institute for Health and Care Research Health Technology Assessment Program; REVIVED-BCIS2 ClinicalTrials.gov number, NCT01920048.).
Assessing the response of human primary macrophages to defined fibrous architectures fabricated by melt electrowriting
Authors: Carlotta Mondadori, Amit Chandrakar, Silvia Lopa, Paul Wieringa, Giuseppe Talò, Silvia Perego, Giovanni Lombardi, Alessandra Colombini, Matteo Moretti, Lorenzo Moroni
Journal: Bioactive Materials (2022)

The dual role of macrophages in the healing process depends on macrophage ability to polarize into phenotypes that can propagate inflammation or exert anti-inflammatory and tissue-remodeling functions. Controlling scaffold geometry has been proposed as a strategy to influence macrophage behavior and favor the positive host response to implants. Here, we fabricated Polycaprolactone (PCL) scaffolds by Melt Electrowriting (MEW) to investigate the ability of scaffold architecture to modulate macrophage polarization. Primary human macrophages unpolarized (M0) or polarized into M1, M2a, and M2c phenotypes were cultured on PCL films and MEW scaffolds with pore geometries (square, triangle, and rhombus grid) characterized by different angles. M0, M2a, and M2c macrophages wrapped along the fibers, while M1 macrophages formed clusters with rounded cells. Cell bridges were formed only for angles up to 90°. No relevant differences were found among PCL films and 3D scaffolds in terms of surface markers. CD206 and CD163 were highly expressed by M2a and M2c macrophages, with M2a macrophages presenting also high levels of CD86. M1 macrophages expressed moderate levels of all markers. The rhombus architecture promoted an increased release by M2a macrophages of IL10, IL13, and sCD163 compared to PCL films. The proangiogenic factor IL18 was also upregulated by the rhombus configuration in M0 and M2a macrophages compared to PCL films. The interesting findings obtained for the rhombus architecture represent a starting point for the design of scaffolds able to modulate macrophage phenotype, prompting investigations addressed to verify their ability to facilitate the healing process in vivo.
<scp>HbSC</scp> disease: A time for progress
Authors: Caterina Minniti, Carlo Brugnara, Martin H. Steinberg
Journal: American Journal of Hematology (2022)

Caterina Minniti—Consultancy for Global Blood Therapeutics, Sangamo, SanguineBio, Forma, Agios, NovoNordisk, Emmaus, Novartis. End point adjudicator: Bluebird Bio; Safety Committee: CSL Behring. Carlo Brugnara—Consulting agreement with Pfizer Inc on sickle cell disease. Martin H. Steinberg—Consultant, Vertex, Astellas, Fulcrum. Not applicable.